Sugammadex is marketed as Bridion® and structurally known as compound of formula I, whereas formula I shows the sodium salt of sugammadex. It is an octa substituted γ-cyclodextrin derivative with a lipophilic core and a hydrophilic periphery.

The chemical structure of cyclodextrins (CD) contains a cyclic oligosaccharides composed of α-(1,4) linked glucopyranose subunits. According to the general accepted nomenclature of cyclodextrins, an α (alpha)-cyclodextrin is a 6-membered ring molecule, a β (beta)-cyclodextrin is a 7-membered ring molecule and a γ (gamma)-cyclodextrin is a 8-membered ring molecule. Cyclodextrins are useful molecular chelating agents. They possess a cage-like supramolecular structure. As a result of molecular complexation phenomena CDs are widely used in many industrial products, technologies and analytical methods.
Sugammadex contains substituted γ-cyclodextrin with eight recurring amylose units each with five asymmetric carbon atoms, in total forty asymmetric carbon atoms for the whole molecule. The original configuration of all asymmetric carbon atoms is retained during the synthetic manufacturing process.
According to various disclosures, including disclosures associated with Bridion®, suganimadex is a potent and effective agent for the reversal of neuromuscular blockade induced by the steroidal neuromuscular blocking agents (NMBA) such as rocuronium, vecuronium and pipecuronium.
Sugammadex was at least disclosed as early as the publication of WO2001/40316A1 (hereinafter referred as WO'316). This publication discloses a process for preparation of sugammadex which involves iodination of dry γ-cyclodextrin to obtain 6-per-deoxy-6-per-iodo-γ-cyclodextrin as a yellow solid. The 6-per-deoxy-6-per-iodo-γ-cyclodextrin was dissolved in dimethylformamide and added slowly to a mixture of 3-mercaptopropionic acid and sodium hydride in dry dimethylformamide. The obtained mixture was heated at 70° C. for 12 Hours. The mixture was cooled and water was added to the mixture. The volume of the mixture was reduced under vacuum by evaporation followed by addition of ethanol to precipitate sugammadex.
The process disclosed in WO2001/40316A1 suffers from the following disadvantages outlined below;
(i) The purity of sugammadex is low (about 88.75 area-% HPLC).
(ii) The use of pyrophoric sodium hydride is also not recommended as it forms explosive hydrogen gas, involves addition of mineral oil to the reaction mixture and is also associated with extensive foaming.
(iii) The process requires the distillation of high boiling point solvent such as water, which is time and energy consuming.
(iv) The reaction time of 6-per-deoxy-6-per-iodo-γ-cyclodextrin with 3-mercaptopropionic acid is also high (about 12 Hours).
WO2012/025937A1 (hereinafter referred as WO'937) discloses the preparation of sugammadex by chlorination of γ-cyclodextrin with phosphorous pentachloride in dimethylformamide, after completion of the chlorination the solvent was removed to obtain a viscous residue. The viscous residue was diluted with water followed by adjusting the pH 8 with 5M sodium hydroxide to obtain slurry, it was then filtered, washed with water and dried to give 6-per-deoxy-6-per-chloro-γ-cyclodextrin. The chlorinated γ-cyclodextrin was dissolved in dimethylformamide and added slowly to a mixture of 3-mercaptopropionic acid and sodium hydride in dimethylformamide. The obtained mixture was heated at 70-75° C. for 12 Hours. The dimethylformamide was partially removed then diluted with ethanol to obtain a precipitate. The precipitate is stirred for one hour and filtered to obtain crude sugammadex. The crude sugammadex was purified over silica gel and Sephadex G-25® column using water as eluent.
The process disclosed in WO2012/025937A1 suffers from the following disadvantages outlined below;
(i) The purity of sugammadex is about 94.35 area-% HPLC.
(ii) The procedure requires the utilization of chromatographic techniques for purification of the crude sugammadex, which are costly and hard to implement in the industrial production scale.
(iii) The use of pyrophoric sodium hydride is also not recommended as it forms explosive hydrogen gas, involves addition of mineral oil to the reaction mixture and is also associated with extensive foaming.
(iv) The process requires the distillation of high boiling point solvent such as dimethylformamide, which is time and energy consuming.
(v) The reaction time of 6-per-deoxy-6-per-chloro-γ-cyclodextrin with 3-mercaptopropionic acid is also high (about 12 Hours).
WO2014/125501A1 (hereinafter referred as WO'501) discloses the preparation of sugammadex by chlorination of γ-cyclodextrin with phosphorous pentachloride in dimethylformamide. After completion of the chlorination, the mixture was quenched with water. The obtained mixture was hydrolyzed with aqueous sodium hydroxide solution, filtered, washed repeatedly with water and dried to give 6-per-deoxy-6-per-chloro-γ-cyclodextrin. The chlorinated γ-cyclodextrin was added slowly to a mixture of 3-mercaptopropionic acid and sodium methoxide in methanol and dimethylformamide, then heated to 75-80° C. and maintained at 75-80° C. for 12 to 14 Hours to give crude sugammadex. The crude sugammadex was purified by treating it with activated carbon in a mixture of water and methanol.
The process disclosed in WO2014/125501A1 suffers from the following disadvantages outlined below;
(i) The purity of sugammadex is 88.50 area -% HPLC.
(ii) The reaction time of 6-per-deoxy-6-per-chloro-γ-cyclodextrin with 3-mercaptopropionic acid is also high (about 12 to 14 Hours).
CN104844732A2 discloses an alternative process for the preparation of sugammadex by reacting 6-per-deoxy-6-per-chloro-γ-cyclodextrin with thiourea in dimethylformamide at 90° C. for 12 Hours. After completion of the reaction, the solvent was partially evaporated followed by addition of ethanol to obtain a precipitate. The resulting solid precipitate was treated with aqueous sodium hydroxide solution followed by adjusting the pH 2 with hydrochloric acid. The ethanol was added to the mixture to obtain a solid residue, which was recrystallized in water to obtain 6-per-deoxy-6-per-mercapto-γ-cyclodextrin.
The 6-per-deoxy-6-per-mercapto-γ-cyclodextrin was reacted with acrylic acid in water under UV light exposure at 20° C. for 6 Hours. The pH of the solution was adjusted to 9 with aqueous sodium hydroxide solution followed by filtering the solution from nanofiltration membrane to obtain sugammadex.
The alternate process disclosed in CN104844732A2 involves specific techniques and instrument for the preparation of sugammadex, which are difficult to implement and control in the industrial scale.
Thus, the prior art procedures for the preparation of sugammadex suffers from the following disadvantages outlined below;
(i) The obtained purity of sugammadex is not satisfactory.
(ii) The reaction time of 6-per-deoxy-6-per-halo-γ-cyclodextrin with 3-mercaptopropionic acid is also very high and not suitable for large scale production.
(iii) The use of pyrophoric reagents such as sodium hydride is also not recommended as their handling is difficult at large scale production of sugammadex.
(iv) The use of special techniques such as chromatographic purification and utilization of UV light are difficult to implement and control in the industrial scale.
Finally, the longer time duration, handling of reagents, utilization of special. techniques and lower purity of sugammadex are not desirable for the preparation of sugammadex.